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Costimulation of T-Cell Activation and Virus Production by B7 Antigen on Activated CD4+ T Cells from Human Immunodeficiency Virus Type 1-Infected Donors OMAR K

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Costimulation of T-Cell Activation and Virus Production by B7 Antigen on Activated CD4+ T Cells from Human Immunodeficiency Virus Type 1-Infected Donors OMAR K Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11094-11098, December 1993 Immunology Costimulation of T-cell activation and virus production by B7 antigen on activated CD4+ T cells from human immunodeficiency virus type 1-infected donors OMAR K. HAFFAR, MOLLY D. SMITHGALL, JEFFREY BRADSHAW, BILL BRADY, NITIN K. DAMLE*, AND PETER S. LINSLEY Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121 Communicated by Leon E. Rosenberg, August 3, 1993 (receivedfor review April 29, 1993) ABSTRACT Infection with the human immunodeficiency sequence (CTLA-4) (34), a protein structurally related to virus type 1 (HIV-1) requires T-cefl activation. Recent studies CD28 but only expressed on T cells after activation (12). have shown that interactions of the T-lymphocyte receptors CTLA-4 acts cooperatively with CD28 to bind B7 and deliver CD28 and CTLA-4 with their counter receptor, B7, on antigen- T-cell costimulatory signals (13). presenting cells are required for optimal T-cell activation. Here Because of the importance of the CD28/CTLA-4 and B7 we show that HIV-1 infection is associated with decreased interactions in immune responses, it is likely that these expression of CD28 and increased expression of B7 on CD4+ interactions are also important during HIV-1 infection. Stud- T-cell lines generated from seropositive donors by afloantigen ies with anti-CD28 monoclonal antibodies (mAbs) suggested stimulation. Loss of CD28 expression was not seen on CD4+ a role for CD28 in up-regulating HIV-1 long terminal repeat- T-ceU lines from seronegative donors, but up-regulation of B7 driven transcription of a reporter gene in leukemic cell lines expression was observed upon more prolonged culture. Both (14). Groux et al. (15) showed that CD28 triggering with T-ceUl proliferation and interleukin 2 mRNA accumulation in specific mAbs prevented activation-induced cell death in HlIV--infected cultures required costimulation with exogenous T-cell cultures from HIV-1-infected donors. The role ofB7 in B7 because these events were blocked by CTLA4Ig, a soluble HIV-1 infection has not been studied, but cultured cell lines form of CTLA-4 that binds B7 with high avidity. In contrast, infected with another human lymphocyte-specific retrovirus, levels ofHIV-1 RNA were not affected by CTLA4Ig, indicating human T-cell lymphotropic virus type 1 (HTLV-1), ex- that regulation of virus transcription in these cultures did not pressed the B7 protein on their surface (16). More recently, depend upon CD28-B7 engagement. Infected T cells could Freeman et al. (17) showed that several HTLV-1-transformed present alloantigen to fresh, uninfected CD4+ T cells, leading T-cell lines expressed mRNAs for B7 and CTLA-4 but not for to increased proliferation and virus spread to the activated CD28. cells. Both of these events were blocked by CTLA4Ig. Thus, We studied the expression and function of CD28/CTLA-4 chronic activation of HIV-1-infected CD4+ T cells reduces and B7 during HIV-1 infection. Specifically, we investigated expression of CD28 and increases expression of B7, thereby like infection with HTLV-1, enabling these T cells to become antigen-presenting ceOls for whether infection with HIV-1, uninfected CD4+ T cells; this might be another mechanism for was associated with increased expression of B7 on T cells, HIV-1 transmission via T-cell-T-cell contact. and if so, whether this might have functional consequences. We generated primary cultures of CD4+ T cells from HIV- 1-infected individuals by alloantigen stimulation, which pro- Infection with the human immunodeficiency virus type 1 with a (HIV-1) leads to a reduction of CD4+ T cells and a loss of vided a homogeneous population of primary T cells immune competency (1). HIV-1-infected individuals exhibit high frequency of HIV-1 infection. a marked deficiency in their ability to respond to recall antigens (e.g., tetanus toxoid) (2). Analysis ofHIV-1-infected MATERIALS AND METHODS cells in vitro has shown defects in T-cell activation and signal transduction (3). Despite the immune defects caused by mAbs and Soluble Receptors. Origins of the mAbs used, HIV-1 infection, induction and spread of the virus requires G17-2 (anti-CD4), G10-1 (anti-CD8), 60.1 (anti-CD11b), 63D3 T-cell activation (4-6). Thus, HIV-1 infection is intimately (anti-CD14), FC2 (anti-CD16), iF5 (anti-CD20), HB1Oa (anti- involved with function of the immune system. MHCII), and 9.3 (anti-CD28) have been presented (11, 18). Optimal antigenic stimulation of CD4+ T cells requires (i) mAb 11D4 (anti-CTLA-4) has been described (13). Anti-CD3 engagement ofthe T-cell receptor-CD3 complex by antigenic mAb Leu-4 conjugated to peridinin chlorophyll protein peptides presented in the context ofmajor histocompatibility (PerCP) and anti-B7 mAb BB1 were purchased from Becton complex (MHC) molecules, and (ii) additional costimulatory Dickinson. Anti-HIV-1 mAb 25-3 was reactive with the signals provided by engagement of accessory receptors on HIV-1 core protein p24 (Genetic Systems, Seattle). Human the T-cell surface with counter receptors on antigen- CTLA4Ig (the soluble form of CTLA-4 that binds B7) has presenting cells (for review, see ref. 7). In addition to been described (12). lymphocyte function-associated antigen 1 (LFA-1) and CD2 (for review, see ref. 7), recent work has elucidated the Abbreviations: HIV-1, human immunodeficiency virus type 1; importance ofthe CD28 receptor in T-cell-dependent immune HTLV-1, human T-cell lymphotropic virus type 1; mAb, monoclonal responses (8, 9). A counter receptor for CD28 is the B7 antibody; IL-2, interleukin 2; CTLA-4, cytolytic T-lymphocyte- molecule expressed on activated antigen-presenting cells (10, associated sequence; FITC, fluorescein isothiocyanate; CTLA4Ig, 11). B7 also binds to cytolytic T-lymphocyte-associated soluble form ofCTLA-4 that binds B7; LFA-1, lymphocyte function- associated antigen 1; MLC, mixed lymphocyte cultures; MHC, major histocompatibility complex; EBV-LCL, Epstein-Barr virus- The publication costs of this article were defrayed in part by page charge transformed B cell(s). payment. This article must therefore be hereby marked "advertisement" *Present address: Wyeth-Ayerst Research, CN 8000, Princeton, NJ in accordance with 18 U.S.C. §1734 solely to indicate this fact. 08543-8000. 11094 Downloaded by guest on October 1, 2021 Immunology: Haffar et al. Proc. Natl. Acad. Sci. USA 90 (1993) 11095 Generation of Alloantigen-Primed T-Cell Lines. CD4+ T A CD2 CD28 LFA-1 MHC Class 11 lymphocytes were isolated from peripheral blood mononu- clear cells from HIV-1-seronegative and -seropositive do- 806 nors, as described (18). Purified CD4+ T cells (>90% pure) were cocultured with irradiated (10,000 rads; 1 rad = 0.01 Gy) Epstein-Barr virus-transformed B cells (EBV-LCL) from a Z29 E; seronegative donor at weekly intervals. After the initial stimulation, the ratio ofstimulators to responders was altered from 1:2 to 1:5 for all subsequent stimulations, and culture Z39 Z L L1 = medium (RPMI 1640 medium/10%o human serum) was sup- plemented with human interleukin 2 (IL-2) at 10 units/ml. Expanded T cells were collected and depleted of CD8+ T Z44 0 cells by complement lysis after mAb G10-1 binding. 1 2 0 30 1 30 1 2 3 Cocultivation and Mixed Lymphocyte Response Assays. Log Fluorescence Intensity Irradiated (10,000 rads) infected alloreactive T cells were used as stimulator cells in mixed lymphocyte cultures (MLC) B with freshly isolated uninfected CD4+ T cells. The responder cells were derived from the same seronegative donor as the Z64 CD3 CD4 CD28 B7 B cells used in the alloactivation of the HIV-i-infected cells. 2Wk A A The MLC were maintained in culture medium with or without CTLA4Ig (10 ,g/ml). Cell proliferation was measured by 3 Wk -AA l [3H]thymidine incorporation, and HIV-1 production was measured by evaluating the p24 concentrations in the culture Z39 medium using specific enzyme immunoassay (5). ,-II 77A7/\ I\ L 11/1- Immunostaining of Cell Surface-Associated Proteins. Cell- .. surface expression of proteins was evaluated by multicolor 3Wk E -I immunofluorescent staining. After staining, cells were z washed with phosphate-buffered saline and fixed overnight 4Wk wD[X L l with 2% paraformaldehyde solution, pH 7.2, at 40C. Intact cells were analyzed by using either an EPICS V (Coulter) or 400 FACScan (Becton Dickinson) instrument. 2 Wk A 1] A 11A I RNA Blot Analysis. RNA was prepared from the alloreac- tive cell lines at various times during the fourth round of 3 Wk A -Al stimulation, fractionated by electrophoresis, and transferred to nitrocellulose filters as described (9). The filters were probed for various RNAs as described (9, 13). The HIV probe 1 2 3 1 2 3 1 2 3 1 2 3 was a 3.1-kb DNA fragment excised from the gag open Log Fluorescence Intensity reading frame by digestion of the plasmid pMgtre (provided with BssHII and Xba FIG. 1. (A) Cell-surface expression of specific receptors in HIV- by Alan Senear, Bristol-Myers Squibb) 1-infected and -uninfected alloantigen-primed CD4+ T-cell lines. I. Cell-surface expression of accessory molecules CD2, CD28, and PCR Analysis. Presence of B7-specific message was eval- LFA-1, as well as MHC class II protein, was evaluated in HIV-1- uated by PCR of cDNA generated from reverse transcription infected (Z29, Z39, and Z44) and uninfected (806) lines at day 7 ofthe of cellular RNA fractions (19). The primers used were as fourth round of stimulation using fluorescein isothiocyanate (FITC)- follows: for B7, 5'-CTGAGCTCTATGCTGTTAGC-3' conjugated mAbs. (B) Kinetic analysis of down-regulation of CD28 (sense) and 5'-ACAGAATTCTGCGGACACTGTTATA- and up-regulation of the counter receptor B7.
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